Crosstalk between degradation and bioenergetics: how autophagy and endolysosomal processes regulate energy production.

Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis.

Drosophila tweety facilitates autophagy to regulate mitochondrial homeostasis and bioenergetics in Glia.

Mitochondria support the energetic demands of the cells. Autophagic turnover of mitochondria serves as a critical pathway for mitochondrial homeostasis. It is unclear how bioenergetics and autophagy are functionally connected.

Regulation of longevity by depolarization-induced activation of PLC-β-IPR signaling in neurons.

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in glutamatergic neurons.

Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes.

Most common neurodegenerative diseases (NDs) are characterized by deposition of protein aggregates that are resulted from misfolding, dysregulated trafficking, and compromised proteolytic degradation. These proteins exert cellular toxicity to a broad range of brain cells and are found in both neurons and glia. Extracellular monomeric and oligomeric ND-associated proteins are taken up by astrocytes, the most abundant glial cell in the brain.

Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets.

HRAS-driven cancer cells are vulnerable to TRPML1 inhibition.

By serving as intermediaries between cellular metabolism and the bioenergetic demands of proliferation, endolysosomes allow cancer cells to thrive under normally detrimental conditions. Here, we show that an endolysosomal TRP channel, TRPML1, is necessary for the proliferation of cancer cells that bear activating mutations in Expression of , which encodes TRPML1, is significantly elevated in -positive tumors and inversely correlated with patient prognosis. Concordantly, knockdown or TRPML1 inhibition selectively reduces the proliferation of cancer cells that express oncogenic, but not wild-type, Mechanistically, TRPML1 maintains oncogenic HRAS in signaling-competent nanoclusters at the plasma membrane by mediating cholesterol de-esterification and transport.

Author Correction: TRPC5 channels participate in pressure-sensing in aortic baroreceptors.

This corrects the article DOI: 10.1038/ncomms11947.

Lysosomal Degradation Is Required for Sustained Phagocytosis of Bacteria by Macrophages.

Clearance of bacteria by macrophages involves internalization of the microorganisms into phagosomes, which are then delivered to endolysosomes for enzymatic degradation. These spatiotemporally segregated processes are not known to be functionally coupled. Here, we show that lysosomal degradation of bacteria sustains phagocytic uptake.

TRPC5 channels participate in pressure-sensing in aortic baroreceptors.

Blood pressure is maintained within a normal physiological range by a sophisticated regulatory mechanism. Baroreceptors serve as a frontline sensor to detect the change in blood pressure. Nerve signals are then sent to the cardiovascular control centre in the brain in order to stimulate baroreflex responses.

Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction.

Here, we evaluate the mechanisms underlying the neurodevelopmental deficits in Drosophila and mouse models of lysosomal storage diseases (LSDs). We find that lysosomes promote the growth of neuromuscular junctions (NMJs) via Rag GTPases and mechanistic target of rapamycin complex 1 (MTORC1). However, rather than employing S6K/4E-BP1, MTORC1 stimulates NMJ growth via JNK, a determinant of axonal growth in Drosophila and mammals.

SIGNAL TRANSDUCTION. Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling.

Plasma membrane depolarization can trigger cell proliferation, but how membrane potential influences mitogenic signaling is uncertain. Here, we show that plasma membrane depolarization induces nanoscale reorganization of phosphatidylserine and phosphatidylinositol 4,5-bisphosphate but not other anionic phospholipids. K-Ras, which is targeted to the plasma membrane by electrostatic interactions with phosphatidylserine, in turn undergoes enhanced nanoclustering.

Plasma membrane mechanical stress activates TRPC5 channels.

Mechanical forces exerted on cells impose stress on the plasma membrane. Cells sense this stress and elicit a mechanoelectric transduction cascade that initiates compensatory mechanisms. Mechanosensitive ion channels in the plasma membrane are responsible for transducing the mechanical signals to electrical signals.

The role of TRPMLs in endolysosomal trafficking and function.

Members of the Transient Receptor Potential-Mucolipin (TRPML) constitute a family of evolutionarily conserved cation channels that function predominantly in endolysosomal vesicles. Whereas loss-of-function mutations in human TRPML1 were first identified as being causative for the lysosomal storage disease, Mucolipidosis type IV, most mammals also express two other TRPML isoforms called TRPML2 and TRPML3. All three mammalian TRPMLs as well as TRPML related genes in other species including Caenorhabditis elegans and Drosophila exhibit overlapping functional and biophysical properties.

A TRPV channel in Drosophila motor neurons regulates presynaptic resting Ca2+ levels, synapse growth, and synaptic transmission.

Presynaptic resting Ca(2+) influences synaptic vesicle (SV) release probability. Here, we report that a TRPV channel, Inactive (Iav), maintains presynaptic resting [Ca(2+)] by promoting Ca(2+) release from the endoplasmic reticulum in Drosophila motor neurons, and is required for both synapse development and neurotransmission. We find that Iav activates the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin, which is essential for presynaptic microtubule stabilization at the neuromuscular junction.

Drosophila TRPML forms PI(3,5)P2-activated cation channels in both endolysosomes and plasma membrane.

Transient Receptor Potential mucolipin (TRPML) channels are implicated in endolysosomal trafficking, lysosomal Ca(2+) and Fe(2+) release, lysosomal biogenesis, and autophagy. Mutations in human TRPML1 cause the lysosome storage disease, mucolipidosis type IV (MLIV). Unlike vertebrates, which express three TRPML genes, TRPML1-3, the Drosophila genome encodes a single trpml gene.

Feast or famine: role of TRPML in preventing cellular amino acid starvation.

Lysosomal storage diseases are metabolic disorders characterized by the accumulation of acidic vacuoles, and are usually the consequence of the deficiency of an enzyme responsible for the metabolism of vesicular lipids, proteins or carbohydrates. In contrast, mucolipidosis type IV (MLIV), results from the absence of a vesicular Ca ( 2+) release channel called mucolipin 1/transient receptor potential mucolipin 1 (MCOLN1/TRPML1) which is required for the fusion of amphisomes with lysosomes. In Drosophila, ablation of the MCOLN1 homolog (trpml) leads to diminished viability during pupation when the animals rely on autophagy for nutrients.

Drosophila TRPML is required for TORC1 activation.

Loss-of-function mutations in TRPML1 (transient receptor potential mucolipin 1) cause the lysosomal storage disorder, mucolipidosis type IV (MLIV). Here, we report that flies lacking the TRPML1 homolog displayed incomplete autophagy and reduced viability during the pupal period--a phase when animals rely on autophagy for nutrients. We show that TRPML was required for fusion of amphisomes with lysosomes, and its absence led to accumulation of vesicles of significantly larger volume and higher luminal Ca(2+).

Structural basis for GTP-dependent dimerization of hydrogenase maturation factor HypB.

Maturation of [NiFe]-hydrogenase requires the insertion of iron, cyanide and carbon monoxide, followed by nickel, to the catalytic core of the enzyme. Hydrogenase maturation factor HypB is a metal-binding GTPase that is essential for the nickel delivery to the hydrogenase. Here we report the crystal structure of Archeoglobus fulgidus HypB (AfHypB) in apo-form.

Heteromeric TRPV4-C1 channels contribute to store-operated Ca(2+) entry in vascular endothelial cells.

There is controversy as to whether TRP channels participate in mediating store-operated current (I(SOC)) and store-operated Ca(2+) entry (SOCE). Our recent study has demonstrated that TRPC1 forms heteromeric channels with TRPV4 in vascular endothelial cells and that Ca(2+) store depletion enhances the vesicle trafficking of heteromeric TRPV4-C1 channels, causing insertion of more channels into the plasma membrane in vascular endothelial cells. In the present study, we determined whether the enhanced TRPV4-C1 insertion to the plasma membrane could contribute to SOCE and I(SOC).